The introduction of cyclosporine for immunosuppression during the 1980's revived interest in transplanting organs and tissues, specifically, the liver, pancreas, heart, lung and heart-lung. However, preservation methods that are successful for kidneys have proven unsuccessful for these other organs. Until recently, the clinical preservation of the heart, liver and pancreas was kept to a minimum and to no longer than six to ten hours. These organs are more complex to transplant than kidneys, and invariably the operations are performed during the night when operating rooms are available in the donor hospitals. Short preservation times for heart and liver also necessitate two surgical teams, one for the donor and another for the recipient. Extending preservation time for these organs to thirty hours would have the same impact on their transplantation as it did on kidney transplantation, namely, increasing organ availability, decreasing organ wastage, increasing organ sharing, and reducing costs.
A preservation solution useful for all donor organs, both for in situ organ cooling in the donor and for cold storage after the organ is harvested is available from E. I. du Pont de Nemours and Co. under the trademark VIASPAN.TM. and disclosed in U.S. Pat. No. 4,879,283. Solution for the Preservation of Organs, issued Nov. 7, 1989, U.S. Pat. No. 4,873,230, Composition for the Preservation of Organs, issued Oct. 10, 1989, and U.S. Pat. No. 4,798,824, Perfusate for the Preservation of Organs, issued Jan. 17, 1989, discloses a hydroxyethyl starch composition useful in the preservation solution disclosed in U.S. Pat. No. 4,879,283. The solution of U.S. Pat. No. 4,879,283 has greatly extended the preservation time of organs intended for transplantation, extending the viability of livers, for example, from six to ten hours to over twenty-four hours. This has allowed sufficient time for compatibility testing of the donor and recipient, increased organ availability, decreased organ wastage, and aided in reducing the cost of a transplant. Current practice is to rinse such preservation solutions from the organ with a Ringer's solution prior to transplanting the organ into a recipient. While the solution of U.S. Pat. No. 4,879,283 has been effective in extending the preservation time of organs intended for transplantation, cell injury still occurs. Therefore, a further reduction in cell injury and increased survival time is desirable.
An injury characterized by loss of endothelial cell viability occurs after cold ischemic storage of rat livers for eight or more hours in Euro-Collins solution or sixteen or more hours in Du Pont VIASPAN.TM. solution (Caldwell-Kenkel, J. C., R. G. Thurman and J. J. Lemasters (1988) Transplantation 45, 834-837; Caldwell-Kenkel, J. C., R. T. Currin, Y. Tanaka, R. G. Thurman and J. J. Lemasters (1989) Hepatology 10, 292-299). Lethal injury does not occur until after the stored organs are reperfused with warm physiologic buffer containing dissolved oxygen. Thus, endothelial cell killing after storage and reperfusion may properly be called a reperfusion injury. Loss of viability is specific for endothelial cells. Hepatic parenchymal cells, Kupffer cells and Ito cells retain viability under conditions where virtually all endothelial cells are nonviable. Moreover, parenchymal cell function remains intact by a number of criteria including oxygen uptake and carbohydrate metabolism (I. Marzi, Z. Zhong, J. J. Lemasters and R. G. Thurman (1989) Transplantation 48, 463-468).
Reperfusion injury after warm ischemia is a phenomenon which has been well documented in heart and other tissues including liver (R. A. Kloner, C. E. Ganote, D. A. Whalen and R. B. Jennings (1974) Am. J. Pathol. 74. 399-422: D. Adkison, M. E. Hollwarth, J. N. Benoit, D. A. Parks, J. M. MoCord and D. N. Granger (1986) Acta Physiol. Scand. Suppl. 548, 101-107). Proposed mechanisms to account for reperfusion injury include: formation of toxic oxygen species (e.g., superoxide, hydrogen peroxide and hydroxyl radical) (J. M. McCord (1985) New Engl. J. Med. 312, 159-164; P. J. Simpson and B. R. Luchesi (1987) J. Lab. Clin. Med. 110, 13-30), disruption of ion homeostasis (G. Bellomo and S. Orrenius (1985) Hepatology 876-882), disruption of volume regulation (C. H. Ganote and J. P. Kaltenbach (1979) J. Molec. Cell. Cardiol. 11, 389-406 (1979)), and mechanical trauma (P. H. Cobbold, P. K. Bourne and K. S. R. Cuthbertson (1985) Basic Res. Cardiol. 80 (Suppl. 2), 155-158). Although prevailing opinion is that acidosis is detrimental during ischemia and organ preservation (W. Rouslin and J. L. Erickson (1986) J. Molec. Cell Cardiol. 18, 1187-1195; F. O. Belzer and J. H. Southard (1988) Transplantation 45, 673-676), our studies indicate that the acidotic pH which occurs naturally during ischemia actually protects against hypoxic cell killing (J. V. Bonventre and J. Y. Cheung (1985) Am. J. Physiol, 249, C149-C159; G. J. Gores, A.-L. Nieminen, K. E. Fleishman, T. L. Dawson, B. Herman and J. J. Lemasters (1989) Am. J. Physiol, 255, C315-C322), an effect mediated by intracellular acidification (G. J. Gores, A.-L. Nieminen, B. E. Wray, B. Herman and J. J. Lemasters (1989) J. Clin. Invest. 83. 386-396). Rather, it is the abrupt return from acidotic to physiologic pH during reperfusion which may precipitate cell killing and contribute to reperfusion injury (R. T. Currin, G. J. Gores, R. G. Thurman and J. J. Lemasters (1989) FASEB J. A626; FASEB J., in press). Other factors which may also contribute to reperfusion injury in livers stored for transplantation surgery include activation of Kupffer cells (J. J. Lemasters, J. C. Caldwell-Kenkel, R. T. Currin, Y. Tanaka, I. Marzi and R. G. Thurman (1989) in Cells of the Hepatic Sinusoid, Vol. 2, E. Wisse, D. L. Knook and K. Decker, Eds., Kupffer Cell Foundation, Rijswijk, The Netherlands, pp. 277-280), disruption of the microcirculation (Y. Takei, I. Marzi, G. J. Gores, R. T. Currin, J. J. Lemasters and R. G. Thurman (1990) in Optical Microscopy for Biology, B. Herman and K. A. Jacobson, Eds., Alan R. Lisa, New York, pp. 487-98), and dysfunction of mitochondria (I. Anundi, J. King, D. A. Owen, H. Schneider, J. J. Lemasters and R. G. Thurman (1987) Am. J. Physiol. 253, G390-G396).